This invention relates to novel compounds having pharmacological activity, to the production thereof, to compositions containing them, and to their use in pharmacy.
A number of compounds have been described which are competitive reversible inhibitors of zinc-containing metalloproteinase enzymes. Such competitive reversible inhibitors are for example those which are inhibitors for the angiotensin converting enzymes (ACE). The utility of such an inhibitor is that it acts to block conversion of the decapeptide angiotensin I to antiotensin II, this last-mentioned compound being a potent pressor substance. ACE inhibitors are therefore potentially of use in the treatment of hypertension. Compounds of this type are for example described in European Patent Application A-0012401. Related inhibitors of the enzyme enkephalinase are described in EPA 0054862.
We have found a group of compounds which act as inhibitors of mammalian collagenase [EC 3.4.24.7] which initiates collagen breakdown. There is now compelling evidence [see for example Arthritis and Rheumatism, 20, 1231, (19770] implicating the involvement of the zinc metalloproteinase, collagenase, as one of the key enzymes in the degradation of articular cartilage and bone in rheumatoid arthritis. Collagen is ont of the major components of the protein matrix of cartilage and bone. Potent inhibitors of collagenase are useful in the treatment of rheumatoid arthritis and associated diseases in which collagenolytic activity is a contributing factor. These diseases include corneal ulceration, periodontal disease, tumour invasion and dystrophic epidermolysis bullosa.
These compounds have substantially no ACE-inhibiting-activity. ACE is a carboxydipeptidase--it cleaves a peptide substrate two residues from the C--terminus. Consequently the C-terminal carboxylic acid is a prime recognition site for both substrates and inhibitors; removal of this ionic binding group drastically reduces inhibitory potency. Collagenase, on the other hand, is an endopeptidase and, as such, has no prerequisite for this binding interaction. Additionally the structure of collagen differs essentially from angiotensin-I, which as noted above is a decapeptide and is cleaved at a phenylalanine-histidine bond to give an octapeptide (angiotensin-II) and a dipeptide (histidylleucine). Collagen is much more complex, in being a triple helix, each strand of the helix containing of the order of 1,000 amino acid residues, the sequence of amino acids around the site cleaved by collagenase being completely different from that around the cleavage site of Angiotensin I. Collagenase cleaves this triple helix at a single locus on each chain approximately two-thirds of the way along the chain from the N-terminus. The amide bond which is cleaved by collagenase is either a glycine-leucine or a glycine-isoleucine bond.